The long-term goal of my laboratory is to elucidate the mechanisms that control mechanotransduction in hair cells, and the defects in this process that cause deafness. We propose here to study the mechanisms that regulate the assembly and function of the hair cell's mechanotransduction complex. We hypothesize that several proteins including TMIE, LHFPL5, TMC1/2, and CIB2 assemble into a mechanotransduction complex in hair cell stereocilia. We predict that some of these proteins contribute to the pore of the transduction channel while other regulate pore properties or link the channel to the tip link and the cytoskeleton. We also predict that a specialized molecular machinery regulates the transport of the components of the mechanotransduction machinery from the cell body into stereocilia. To test our hypothesis, we will use genetically modified combined with biochemical, cell biological and electrophysiological methods to study protein function in protein transport and mechanotransduction. Our preliminary data show the feasibility of our approach. We have new evidence regarding the mechanisms by which components of the mechanotransduction machinery function within the transduction complex and we have identified new proteins that regulate protein transport from the cell body into stereocilia.
Hearing loss is a major health problem that significantly affects the life quality of affected individuals. Many forms of hearing loss are genetic in origin and affect hair cells, the mechanosensors that convert sound induced vibrations into electrical signals. We propose here to study components of the mechanotransduction machinery of hair cells, and how mutations in the genes that encode these components lead to hearing loss, which we anticipate will ultimately lead to better treatment of the disease.
|Liu, Chang; Luo, Na; Tung, Chun-Yu et al. (2018) GRXCR2 Regulates Taperin Localization Critical for Stereocilia Morphology and Hearing. Cell Rep 25:1268-1280.e4|
|Wu, Zizhen; Grillet, Nicolas; Zhao, Bo et al. (2017) Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci 20:24-33|
|Cunningham, Christopher L; Wu, Zizhen; Jafari, Aria et al. (2017) The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells. Elife 6:|
|Zhao, Bo; Wu, Zizhen; Müller, Ulrich (2016) Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function. Elife 5:|
|Zeng, Wei-Zheng; Grillet, Nicolas; Dewey, James B et al. (2016) Neuroplastin Isoform Np55 Is Expressed in the Stereocilia of Outer Hair Cells and Required for Normal Outer Hair Cell Function. J Neurosci 36:9201-16|
|Wu, Zizhen; Müller, Ulrich (2016) Molecular Identity of the Mechanotransduction Channel in Hair Cells: Not Quiet There Yet. J Neurosci 36:10927-10934|
|Zhao, Bo; Müller, Ulrich (2015) The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34:172-9|
|Müller, Ulrich; Barr-Gillespie, Peter G (2015) New treatment options for hearing loss. Nat Rev Drug Discov 14:346-65|
|Beurg, Maryline; Xiong, Wei; Zhao, Bo et al. (2015) Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc Natl Acad Sci U S A 112:1589-94|
|Zhao, Bo; Wu, Zizhen; Grillet, Nicolas et al. (2014) TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84:954-67|
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